Lung cancer is associated with high mortality rates; oral targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors (e.g., gefitinib, erlotinib, afatinib) improve survival for non-small cell lung cancer (NSCLC) patients, bt this comes at a cost. NSCLC patients taking oral EGFR inhibitor therapy are challenged with symptoms related to EGFR inhibition. Findings from the applicant's dissertation and the literature suggest the most debilitating side effect is a painful papulopustular rash. The rash has been linked with improved patient outcomes, but it also decreases quality of life, increases healthcare-related costs, and results in reductions in dose or discontinuation of therapy. Biological mechanism(s) underlying development and severity of EGFR inhibitor-related rash are not well understood. This creates a critical barrier to development of interventions to reduce or eliminate side effects related to EGFR inhibition. This study seeks to address this gap by investigating genetic, clinical, and biomarker correlates of EGFR inhibitor-related rash. First, th applicant will test the hypothesis that circulating soluble EGFR (sEGFR) levels are associated with development and severity of EGFR inhibitor-related rash. Serum sEGFR levels will be examined at baseline prior to therapy initiation, and then at selected time points during the first four months of treatment. Eligible participants include adults with NSCLC initiating EGFR inhibitor therapy. Normative sEGFR levels over time will be established in control participants without cancer matched on age, race, and gender. Demographic (e.g., age, race) and clinical (e.g., EGFR mutational status, smoking) information will be used to examine other factors that may contribute to rash development. Training will focus on learning to conduct enzyme-linked immunosorbent assays to measure sEGFR levels and building translational research skills. Second, the applicant will test the hypothesis that there is a unique transcriptional signature in fibroblasts from patients who develop the rash that distinguishes them at a molecular level from those who do not develop the rash. Fibroblasts from skin biopsies collected from the same NSCLC patients and control participants in Aim 1 at baseline will be cultured. We will also examine gene expression profiles in response to erlotinib or vehicle control to gain insight into how erlotinib alters the fibroblast transcriptome in patients who do and do not develop rash. Training will focus on specimen collection/preparation, tissue culture, RNA extraction, and microarray analysis. Careful selection of senior mentors with expertise in genetics of symptoms (e.g., pain), lung cancer, and personalized medicine will guide the applicant in this research, which strongly aligns with the NINR mission by examining the underlying biological basis of symptoms that interfere with patient quality of life and builds upon the applicant's dissertation b focusing on a patient-identified symptom that disrupts medication-taking. New knowledge will provide direction for development of interventions to improve or eliminate treatment-related symptoms, which may reduce burden on patients with cancer and their caregivers.